MassIVE MSV000086739

Partial Public PXD023717

Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor

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Description

AKT activation is a hallmark of IM resistance in GIST. The presence of an additional therapeutic agent could potentially suppress the growth and survival of a clone of cancer cells, which have developed resistance to IM. Simultaneous targeting of AKT in addition to inhibiting KIT with IM has potential to be a promising strategy to prevent the development of secondary resistance to IM. Our group has previously shown significantly enhanced combination effects of IM with MK-2206, an oral pan-AKT inhibitor, in an IM-sensitive xenograft model in vivo, as measured by extended disease stabilization and improved survival. In this study, we evaluated the efficacy of a new selective, allosteric pan-AKT inhibitor, ARQ 751 (Merck, ArQule) in both IM-sensitive and resistant GIST in vivo models, including a GIST patient-derived xenograft (PDX) possessing an exon 9 KIT mutation. We report superior activity of ARQ 751 in combination with IM in a panel of IM-sensitive and IM-resistant GIST cell lines in vitro. This activity is mediated by increased PDCD4 expression leading to increased apoptosis and cell cycle arrest. Furthermore, dual inhibition of KIT and AKT provided impressive diseases stabilization in IM-sensitive GIST xenografts and trends toward stabilization in IM-resistant models in vivo. [doi:10.25345/C5GB7Z] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Gastrointestinal stromal tumor ; AKT ; KIT ; PDCD4

Contact

Principal Investigators:
(in alphabetical order) 		Lori Rink, Fox Chase Cancer Center, USA
Submitting User: alexcampos

Publications

Marya Kozinova, Shalina Joshi, Shuai Ye, Martin G. Belinsky, Dinara Sharipova, Jeffrey M. Farma, Sanjay S. Reddy, Samuel Litwin, Karthik Devarajan, Alex Rosa Campos, Yi Yu, Brian Schwartz, Margaret von Mehren and Lori Rink.
Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor.
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